Use of NK-1 receptor antagonists for treating amnestic disorders

Abstract

The present invention provides methods for the treatment or prevention of amnestic disorders which comprises oral administration of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.

We claim: 
     
       1. A method for the treatment or prevention of an amnestic disorder, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an NK-1 receptor antagonist wherein the NK-1 receptor antagonist is CNS-penetrant as determined by its ability to inhibit NK-1 receptor agonist-induced foot-tapping in the gerbil and is effective in the attenuation of separation-induced vocalisations by guinea-pig pups. 
     
     
       2. A method for the treatment or prevention of an amnestic disorder in a patient who is non-responsive to heterocyclic antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocyclic antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of NK-1 receptor antagonist wherein the NK-1 receptor antagonist is CNS-penetrant as determined by its ability to inhibit NK-1 receptor agonist-induced foot-tapping in the gerbil and is effective in the attenuation of separation-induced vocalisations by guinea-pig pups. 
     
     
       3. A method for the treatment or prevention of an amnestic disorder in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an NK-1 receptor antagonist wherein the NK-1 receptor antagonist is CNS-penetrant as determined by its ability to inhibit NK-1 receptor agonist-induced foot-tapping in the gerbil and is effective in the attenuation of separation-induced vocalisations by guinea-pig pups. 
     
     
       4. A method according to claim 1 wherein the NK-1 receptor antagonist is selected from: 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2, 4-triazolo)methyl)-3-(S)-phenyl-morpholine;   2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl -3-(S)-(4-fluorophenyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(-(S)-(-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)pheny)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;   2-(S)-(1-(R)-(3,5-trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;   2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;   (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-spiro[4.5]decane;   (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl-1-oxa-7-aza-spiro[4.5]decane;   (±)-(2R3R,2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl}-2-phenylpiperidin-3-amine;   and a pharmaceutically acceptable salt thereof.   
     
     
       5. A method according to claim 1 wherein the amnestic disorder is caused by: alcohol and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephalitis and other limbic encephalitis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders; vascular disorders; or pathology around ventricle III.